The process of tumor induction has been broadly divided into two stages: initiation and promotion. Initiation apparently involves irreversible alteration in the genetic material. Promotion appears to be epigenetic and reversible at least in the early stages. Hence, interruption of the process should be feasible at the promotion stage. This project aims to isolate and characterize putative, endogenous tumor promoters and their antagonists and to develop rapid and economical assays for their identification; specifically the detection, isolation, characterization, and study of: (1) the mechanism of 12-0-tetradecanoylphorbol-13-acetate (TPA)-induced inhibition of epidermal growth factor (EGF) binding (TIEB); (2) a compound(s) which can reverse and modulate TIEB at nontoxic doses; (3) membrane receptors of phorbol esters; (4) endogenous ligands (agonists and antagonists) for phorbol receptors; (5) growth factor(s) induced by biologically active phorbol esters; (6) reversal of anchorage-independent growth of transformed cells by differentiation-inducing agents; (7) the metabolism of phorbol diesters; (8) phorbol diester binding protein(s); (9) TPA induction or enhanement of the expression of endogenous oncogenic cellular information; (10) enhancement of carcinogenesis by EGF and other growth factors; and (11) action of retroviruses as promoters in carcinogenesis initiated by chemical or physical agents. Recent results include the following: (1) Specific receptors for phorbol and ingenol esters were solubilized and purified to homogeneity. Their physicochemical and biochemical properties were characterized. It was found that the receptor is a protein kinase. (2) Endogenous ligands from cow milk and murine intestine, pancreas and stomach were purified, identified and characterized. These ligands were found to be mono- and diglycerides with special structural features. (3) Endogenous oncopromotine(s) and oncoretardine(s) have been detected in brain. Their purification and characterization are in progress. (4) A very potent oncostatin (antitumor promoter) is currently being isolated and characteized from clams and other mollusks.